Glaucoma is a degenerative disease of the eye wherein the intraocular pressure is too high to permit normal eye function. As a result, damage may occur to the optic nerve head and result in irreversible loss of visual function. If untreated, glaucoma may eventually lead to blindness. Ocular hypertension, i.e., the condition of elevated intraocular pressure without optic nerve head damage or characteristic glaucomatous visual field defects, is now believed by the majority of ophthalmologists to represent merely the earliest phase in the onset of glaucoma.
Many of the drugs formerly used to treat glaucoma proved to be not entirely satisfactory. The early methods of treatment of glaucoma employing pilocarpine produced undesirable local effects that made this drug, though valuable, unsatisfactory as a first line drug. More recently, clinicians have noted that many .beta.-adrenergic antagonists are effective in reducing intraocular pressure. While many of these agents are effective for this purpose, there exist some patients with whom this treatment is not effective or not sufficiently effective. Many of these agents also have other characteristics, e.g., membrane stabilising activity, that become more apparent with increased doses and render them unacceptable for chronic ocular use.
The .beta.-adrenergic antagonist, timolol, was found to reduce intraocular pressure and to be devoid of many unwanted side effects associated with pilocarpine and, in addition, to possess advantages over many other .beta.-adrenergic antagonists, e.g., to be devoid of local anaesthetic properties, to have a long duration of activity, and to display minimal loss of effect with increased duration of dosing.
Although pilocarpine and .beta.-adrenergic antagonists reduce intraocular pressure, none of these drugs manifests its action by inhibiting the enzyme carbonic anhydrase, and thus they do not take advantage of reducing the contribution to aqueous humor formation made by the carbonic anhydrase pathway.
Agents referred to as carbonic anhydrase inhibitors block or impede this inflow pathway by inhibiting the enzyme carbonic anhydrase. While such carbonic anhydrase inhibitors are now used to treat intraocular pressure by systemic routes, they thereby have the distinct disadvantage of inhibiting carbonic anhydrase throughout the entire body. Such a gross disruption of a basic enzyme system is justified only during an acute attack of alarmingly elevated intraocular pressure, or when no other agent is effective.
For several years, the desirability of directing the carbonic anhydrase inhibitor to only the desired ocular target tissue has been recognised. Because carbonic anhydrase inhibitors have a profound effect in altering basic physiological processes, the avoidance of a systemic route of administration serves to diminish, if not entirely eliminate, those side effects caused by inhibition of carbonic anhydrase such as metabolic acidosis, vomiting, numbness, tingling, general malaise and the like.
Recently, a topically effective carbonic anhydrase inhibitor has become available for clinical use. (S,S)-(-)-5,6-Dihydro-4-ethylamino-6-methyl-4H-thieno[2,3-b]thiopyran-2-su lfonamide-7,7-dioxide hydrochloride (dorzolamide HCl; MK507) is the active ingredient in TRUSOPT.TM. which is prescribed for the treatment of elevated intraocular pressure in ocular hypertension, open-angle glaucoma and pseudo-exfoliative glaucoma. TRUSOPT.TM. Ophthalmic Solution is applied as an isotonic, buffered, slightly viscous, aqueous solution of dorzolamide HCl. Each ml of TRUSOPT.TM. 2% contains 20 mg dorzolamide (22.3 mg dorzolamide HCl). When used as monotherapy, the dose is one drop of TRUSOPT.TM. Ophthalmic Solution in the conjunctival sac of each affected eye three times daily.
The activity of dorzolamide HCl and of other topical carbonic anhydrase inhibitors currently under development wanes 6 to 8 hours post-dose, meaning that as single agents these carbonic anhydrase inhibitors must be administered at least three times a day to maintain the desired lowering of intraocular pressure. The composition of the present invention maintains the desired lowering of intraocular pressure for a full twelve hours. Because of this increased duration of action, the composition disclosed herein is effective when administered only twice a day. Patient compliance is anticipated to be greater with twice a day administration than with three times a day administration.
Grove et al, S.T.P. Pharma Sciences, 2(1), 76-80 (1992) describe the effects of hypotonicity upon a hydroxyethyl cellulose (HEC) solution of the topical carbonic anhydrase inhibitor, 5-(3-dimethylaminoethyl-4-hydroxyphenylsulfonyl)thiophene-2-sulfonamide hydrochloride.
International (PCI) Publication No. WO 94/27578 describes drug delivery compositions comprising a liquid hypotonic solution of at least one hydrophilic polymer of the type which undergoes liquid-gel phase transition gelling in situ in contact with a physiological solution, and a pharmaceutically active compound.
U.S. Pat. No. 4,136,173 (Pramoda et al) published Jan. 23, 1979 describes ophthalmic compositions containing xanthan gum and locust bean gum which are pH sensitive and which gel upon instillation.
U.S. Pat. No. 4,136,177 (Lin et al) published Jan. 23, 1979 describes ophthalmic compositions comprising an ophthalmic drug and xanthan gum.
U.S. Pat. No. 4,136,178 (Lin et al) published Jan. 23, 1979 describes ophthalmic compositions comprising an ophthalmic agent and locust bean gum.
European Patent Specification No. 0 507 224-A describes combinations of gelling polysaccharides and finely divided drug carrier substrates in topical ophthalmic compositions which are adminstrable as a drop and which gel upon instillation.
U.S. Pat. No. 5,318,780 (Viegas et al) published Jun. 7, 1994 also relates to uses of in situ formed gels, in which compositions are prepared combining a film-forming water soluble polymer and an ionic polysaccharide, and optionally a latent counter-ion to gel the polysaccharide upon release of the counter ion.